We propose to continue our investigations of opiate-CNS site interactions, with special emphasis on delineating the nature of the interactions of the newly-discovered opioid peptides (enkephalins and endorphins) and their analogues with CNS sites. The recent discovery of receptors in brain which bound stereospecifically to opiates gave impetus to an intense search for the endogenous ligand of these receptors, and culminated in the discovery of a family of peptides, most of which were found to have amino-acid sequences contained in the 91-amino acid pituitary peptide beta-LPH, and shown to have varying CNS effects following intracerebroventricular or intracerebral (into the periaqueductal gray (PAG) injections. It is likely that beta-LPH is a prohormone for these newly-discovered peptides. Their physiological role in the CNS remains to be fully delineated. Using an improved intracerebral microinjection technique, we were able to demonstrate that the periaqueductal gray mediated morphine effects, i.e., profound analgesia, concurrently with an explosive hyper-reactivity to previously neutral stimuli. Microinjection of the opioid peptides in this area resulted in moderate to pronounced CNS effects, characterized chiefly by sedation, immobility and catalepsy. Beta-LPH (61-91) resulted in the most marked effects, similar to those seen following high doses of neuroleptics. Hyper-reactivity was never observed following microinjection of this peptide. So far, we have found only the periventricular-periaqueductal gray to mediate opiate effects. However, other CNS regions of high opiate receptor binding have been reported. It is likely that an as-yet-unidentified opiate-relevant function (other than analgesia which we have been focussing on in our previous work) is mediated by these CNS regions. We propose to investigate these CNS sites, using multiple assays (including the guinea pig ileum and brain homogenate binding assays).